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Device Profile For reprint orders, please contact [email protected] Biodegradable collagen matrix implant for trabeculectomy Expert Rev. Ophthalmol. 3(6), 613–617 (2008) Joseph R Zelefsky, Wei-Cherng Hsu and Robert Ritch† Author for correspondence Einhorn Clinical Research Center, New York Eye and Ear Infirmary, 310 East 14th Street, NY 10003, USA Tel.: +1 212 673 5140 Fax: +1 212 420 8743 [email protected] † The biodegradable collagen matrix implant, marketed initially as OculusGen™ and currently as Ologen™ and iGen™, is a novel bioengineered implant designed to be used at the time of trabeculectomy. It consists of a collagen-based scaffold containing thousands of microscopic pores. The implant is placed directly over the scleral flap and influences the healing process by forcing fibroblasts and myofibroblasts to grow into the pores and secrete connective tissue in the form of a loose matrix. This results in decreased scar formation and improved surgical success over trabeculectomy performed without the adjunctive use of antifibrotic agents. Preliminary studies have demonstrated that the biodegradable collagen matrix is effective for use in trabeculectomy, although it may be associated with an increased risk of early postoperative hypotony. Future randomized, controlled trials should help determine its place in glaucoma surgery. Keywords : biodegradable collagen • filtering bleb • glaucoma • iGen™ • matrix • microtechnology • OculusGen™ • Ologen™ • tissue bioengineering • trabeculectomy Trabeculectomy currently remains the ‘gold standard’ for filtration surgery. A disadvantage of this procedure is postoperative scarring and fibrosis, leading to bleb failure and elevated intraocular pressure (IOP) [1] . The development of Tenon’s cysts, which contain compressed collagen lamellae and lack an epithelial lining, and scarring at the conjunctiva–Tenon’s–episcleral interface, may prevent the ability of aqueous humor to resorb [2] . Concern over postoperative scarring has led to the widespread intraoperative use of antifibrotic agents, particularly 5-fluorouracil and mitomycin C (MMC). These chemotherapeutic agents inhibit fibroblast activity, reducing postoperative scarring and increasing surgical success rates [3] . However, they bring an increased risk for chronic bleb leaks, hypotony, blebitis and endophthalmitis [4–6] . The need for a balance between improving success while reducing complications has led to the search for an effective method of preventing postoperative fibrosis in a controlled fashion, without incurring the morbidities and side effects associated with antifibrotic agents. Biodegradable collagen matrix implant One solution to this challenge may have its roots in the burgeoning field of tissue bioengineering. Regenerative medicine, the replacement and www.expert-reviews.com 10.1586/17469899.3.6.613 improvement of cells, tissues and organs, promises to become the major focus of medicine in the coming generation. Tissue bioengineering involves the combination of a polymer scaffold with a population of proliferating cells. If the scaffold is biodegradable, it can result in the formation of structures that are remarkably similar to the normal tissue [7] . Broadly speaking, nanotechnology deals with constructs in the order of 100 nm or smaller in size. Microtechnology deals with structures in the order of 100–1000 nm (1 µm). Scaffolds are highly important in tissue bioengineering, drug release and regenerative medicine. Both the scaffold and the seeded cell population play key roles in the generation of composite structures. Recent advances in bioengineering have made it possible to generate de novo tissue through in vitro constructs, typically consisting of a biodegradable polymer and stem or progenitor cells. Examples of bioengineered structures include cartilage, bone, blood and liver. The biodegradable collagen matrix (BCM) implant is marketed, depending on the country, as Ologen™ (Aeon Astron Corporation) or iGen™ (Life Spring Biotech Company), both based in Taipei, Taiwan. It takes advantage of microtechnology and tissue bioengineering by having a molecular structure that permits the © 2008 Expert Reviews Ltd ISSN 1746-9899 613 Device Profile Zelefsky, Hsu & Ritch formation of a spongy filtration bleb without the use of antifibrotic agents. The implant is a 3D porous scaffold made of 1% collagen/C-6-S copolymer with a pore size ranging from 20 µm to 200 µm. It measures 4 × 7 mm and has a cylindrical shape, allowing for easy insertion and manipulation during glaucoma surgery (Figures 1–3) . The implant encourages the formation of a spongy meshwork of fibroblasts and connective tissue in a controlled and organized pattern by forcing fibroblasts and myofibroblasts to only grow into the pores, during the early postoperative period and secrete connective tissue in the form of a loose matrix. By guiding the pattern of cellular migration, it decreases the formation of dense scar tissue. After the polymer scaffold biodegrades, it leaves a milieu of organized fibroblasts, myofibroblasts and extracellular matrix, with less scar formation than would otherwise have occurred (Figure 4) [8] . What results is an elevated bleb with dynamic flow of aqueous humor from the anterior chamber to the subconjunctival space, without the thin-walled, cystic bleb associated with antifibrotics (Figure 5) . The implant also maintains an elevated bleb while the healing process is underway. In trabeculectomy, early inflammation can lead to adhesion of the conjunctiva to the episclera. The implant sits between these two tissue layers, maintaining a prominent space between them, thus forming a mechanical barrier that may prevent adhesions between the conjunctiva and episcleral surface during the early postoperative phase [9] . In animal studies, the implant minimized wound leaks, which can result from inadequate conjunctival closure [9] . Situated between the scleral flap and conjunctiva, the implant limits the amount of aqueous humor flow through the scleral flap, in the early postoperative period, and allows the bleb to maintain an elevated 3D structure as fibroblasts proliferate and lead to wound healing [9] . Elimination of the thin-walled, cystic bleb, characteristic of those obtained with antifibrotics, should also reduce the incidence of late bleb leaks, which are a serious and difficult problem to deal with. Numerous methods have been attempted to repair bleb leaks, including amniotic OculusGen™ implantation Figure 1. Biodegradable collagen matrix implant positioned directly above the scleral flap. 614 Figure 2. The biodegradable collagen matrix implant. membrane grafting [10] , conjunctival grafting [11–13] , conjunctival advancement [14] , fibrinogen glue, application of a bandage contact lens [15] and collagen shield placement [16] . Despite these options, bleb leaks remain difficult to manage and frequently recur after initially successful treatment. Surgical technique Implantation of the BCM is easily adapted to the standard trabeculectomy technique. A conjunctival incision (either fornixor limbal-based) is created. After the conjunctiva and Tenon’s capsule are dissected, a partial-thickness scleral flap is formed. A sharp blade is used to enter the anterior chamber at the base of the scleral flap. A sclerostomy is created with a punch or by en bloc excision, after which the scleral flap is closed with two to four 10–10 nylon sutures. The implant is then placed directly above the scleral flap and the conjunctiva closed (Figure 6) . Research Animal studies Chen et al. performed trabeculectomy with the BCM implant in one eye of 17 rabbits and standard trabeculectomy without antifibrotic agents in the fellow eye as a control [8] . For the first 2 postoperative weeks, IOP was similar in the two groups, then decreased in the implant group as the matrix dissolved, while IOP in the control group progressively elevated to preoperative levels. Another study tested the implant’s ability to minimize bleb leaks. A total of 30 rabbits undergoing trabeculectomy with the implant were compared with a control group of six rabbits undergoing trabeculectomy without it. In both groups, the conjunctiva was incompletely sutured to produce a wound leak. Although the conjunctival defect sealed equally well in both groups, IOP was significantly lower in the implant group after conjunctival healing was complete. The investigators felt that the physical presence of the implant above the scleral flap limited sudden fluctuations in aqueous flow through the flap and allowed healing of the conjunctival defect in a 3D pathway. The control group, on the other hand, healed in a linear fashion, leading to scarring of the bleb [9] . Expert Rev. Ophthalmol. 3(6), (2008) Biodegradable collagen matrix implant for trabeculectomy Device Profile Human studies The BCM implant is now available in Europe and Asia. Although the number of clinical studies is still limited, early results are hopeful. Chen and Hsu reported the preliminary results of their experience in 12 patients. They found a 64% reduction in IOP 4 months after surgery [17] . The average number of glaucoma medications also decreased from 2 to 0.3. There were no intraoperative complications and minimal postoperative complications. Ruokonen et al. reported their experience in 17 patients with open-angle glaucoma. IOP improved from 30 to 14 mmHg after 3 months [18] . The average number of glaucoma medications required decreased from 3.3 to 0.2. Four patients required surgical intervention for hypotony, and two required repositioning of a migrated implant. A total of 11 eyes developed bleb encapsulation with elevated IOP after 1 month. Of these, some responded well to needling and two required further surgery to control IOP. Only two patients required reinstitution of antiglaucoma medications. Another study reported the outcomes of 20 consecutive patients who underwent fornix-based trabeculectomy with implant placement [19] . After 3 months, mean IOP decreased from 33.8 to 13.3 mmHg. Seven patients had hypotony (defined as IOP < 4 mmHg) at some point postoperatively, but only two developed shallow anterior chambers. A total of 80% of the subjects achieved either an IOP of less than 21 mmHg without medications, or a 30% reduction in IOP with or without medications. One patient required a needle revision of the bleb and another required a repeat trabeculectomy with MMC. All patients tolerated the implant well and no systemic adverse effects were noted. In another clinical trial involving 22 eyes with glaucoma, 11 eyes underwent trabeculectomy with MMC and 11 underwent trabeculectomy with the implant [20] . Both groups experienced similar IOP reduction after 30 days. The incidence of shallow anterior chambers was similar between the two groups. Figure 4. Randomized collagen (white arrow) deposited in a prominent bleb (long black arrow) in a rabbit eye that underwent trabeculectomy with biodegradable collagen matrix implantation. A 10–10 nylon suture (20–30 µm diameter, black arrow) is located in the upper right corner. Reprinted with permission from the Association for Research and Vision in Ophthalmology. Researchers in China studied the effects of trabeculectomy with the implant versus trabeculectomy without antifibrotics. A total of 30 eyes were included in each group. The mean IOP was significantly lower in the implant group after 6 months of follow-up. The risk of bleb failure was 30% lower in the implant group [21] . The BCM implant is also being used in cases of cataract extraction combined with trabeculectomy. Grewal et al. studied ten patients with primary open-angle glaucoma who were undergoing combined phacoemulsification with trabeculectomy and implant placement [22] . At 3 months postoperatively, the mean IOP had improved from 20 to 9 mmHg and the mean number of topical glaucoma medications needed was reduced from 2.7 to 0.9. No complications were encountered. Conclusion Figure 3. Scanning electron micrograph of the biodegradable collagen matrix implant, demonstrating the microscopic pores that will control the pattern of scar tissue formation. www.expert-reviews.com The BCM implant invokes the concepts of tissue bioengineering to promote successful filtration surgery in patients with glaucoma. The implant induces formation of a diffuse and elevated bleb by guiding the formation of scar tissue in a physiological pattern. Animal studies and preliminary results with humans suggest that trabeculectomy with BCM implant placement may reduce IOP as well as trabeculectomy with MMC, the current gold standard of glaucoma surgery. Randomized, controlled prospective trials have not yet been performed and are necessary. Furthermore, some studies have reported a relatively high incidence of early hypotony after trabeculectomy with implant placement. Larger-scale clinical trials and long-term follow-up data will be necessary to better evaluate its safety and clinical efficacy. 615 Device Profile Zelefsky, Hsu & Ritch Figure 5. Postoperative clinical photograph of a patient who underwent trabeculectomy with biodegradable collagen matrix implant placement. The bleb is elevated and spongy, and lacks the thin-walled, ischemic appearance that is characteristic of antifibrotic usage. Photograph courtesy of Peter Rieck, MD. Expert commentary The early data presented previously suggest that BCM implants have the potential to play an important role in glaucoma surgery. The past years have seen a tremendous proliferation in the use of 5-fluorou racil and MMC, and this has led to an increased incidence of several sight-threatening complications associated with these potent medications. The implant’s ability to improve bleb survival without incurring the risks associated with antifibrotic agents will hopefully increase interest in this device. Randomized, controlled studies will help delineate the implant’s role in glaucoma surgery. Currently, long-term data are lacking. Moreover, additional prospective studies are necessary to confirm the incidence of early postoperative hypotony and, if substantiated, determine its underlying mechanism. Figure 6. The surgeon places a biodegradable collagen matrix implant in the eye of a patient undergoing fornix-based trabeculectomy. Photograph courtesy of Henry Shen-Lih Chen, MD. possible risk of early postoperative hypotony, clinicians who use the implant should plan accordingly as they care for the patient during the first few weeks after surgery. Another factor that will inevitably play a role in the future of this device is its cost. Currently, it has been estimated that the cost of the device may range between US$300 and $400. Whether insurance companies and government-managed healthcare plans pay for this device remains to be seen. Due to the lack of current long-term data, one can only speculate whether trabeculectomy with BCM implants alone will be sufficient to control IOP in patients with advanced glaucoma. Early data, however, support the concept that microtechnology and nanotechnology will play increasingly important roles in ophthalmology. Financial & competing interests disclosure Five-year view As clinicians become familiar with the implant and use it with greater frequency, we expect to see a decrease in the incidence of bleb leaks, bleb-related ocular infections and other long-term complications associated with antifibrotic usage. Given the Robert Ritch is a consultant to Aeon Astron Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Key issues • Trabeculectomy with antifibrotic agents is the current gold standard for glaucoma surgery and is associated with an increased risk for chronic bleb leaks, hypotony, blebitis and endophthalmitis compared with trabeculectomy without antifibrotic agents. • The biodegradable collagen matrix is a collagen-based scaffold containing thousands of microscopic pores and is implanted above the scleral flap during trabeculectomy in lieu of antifibrotic agents. • The pores guide the pattern of cellular migration and lead to the development of a milieu of organized fibroblasts, myofibroblasts and extracellular matrix, as well as decreased scar tissue formation. • The result is the development of an elevated, spongy bleb without the thin-walled, cystic appearance associated with antifibrotic usage. • Animal studies and preliminary human results suggest that trabeculectomy with biodegradable collagen matrix implant placement may be as successful as trabeculectomy with antifibrotic medications. • Although some preliminary studies in humans report no complications, others reveal an increased incidence of early postoperative hypotony in patients who underwent trabeculectomy with implant placement. 616 Expert Rev. Ophthalmol. 3(6), (2008) Biodegradable collagen matrix implant for trabeculectomy References Papers of special note have been highlighted as: • of interest •• of considerable interest 1 Arici MK, Demircan S, Topalkara A. Effect of conjunctival structure and inflammatory cell counts on intraocular pressure after trabeculectomy. Ophthalmologica 213, 371–375 (1999). • Publication suggesting that the potential benefits of the Ologen implant extend beyond preservation of bleb function. 10 Budenz DL, Barton K, Tseng SCG. Amniotic membrane transplantation for repair of leaking glaucoma filtering blebs. Am. J. Ophthalmol. 130, 580–588 (2000). 11 Buxton JN, Lavery KT, Liebmann JM et al. Reconstruction of filtering blebs with free conjunctival autografts. Ophthalmology 101, 635–639 (1994). 12 Schnyder CC, Shaarawy T, Ravinet E et al. Free conjunctival autologous graft for bleb repair and bleb reduction after trabeculectomy and nonpenetrating filtering surgery. J. Glaucoma 11, 10–16 (2002). 2 van Buskirk EM. Cysts of Tenon’s capsule following filtration surgery. Am. J. Ophthalmol. 94, 522–527 (1982). 3 Lama PJ, Fechtner RD. Antifibrotics and wound healing in glaucoma surgery. Surv. Ophthalmol. 48, 314–346 (2003). • Well-written and extensive review of antifibrotic agents and their clinical use in glaucoma surgery. 13 DeBry PW, Perkins TW, Heatley G et al. Incidence of late-onset bleb-related complications following trabeculectomy with mitomycin. Arch. Ophthalmol. 120, 297–300 (2002). Wilson MR, Kotas-Neumann R. Free conjunctival patch for repair of persistent late bleb leak. Am. J. Ophthalmol. 117, 569–574 (1994). 14 Burnstein AL, WuDunn D, Knotts SL et al. Conjunctival advancement versus nonincisional treatment for late-onset glaucoma filtering bleb leaks. Ophthalmology 109, 71–75 (2002). 15 Blok MD, Kok JH, van Mil C et al. A use of the Megasoft Bandage Lens for treatment of complications after trabeculectomy. Am. J. 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Biodegradable 3D-porous collagen–glycosaminoglycan scaffold for treatment of refractory glaucoma. Presented at: World Ophthalmology Congress 2008. Hong Kong, 28 June–2 July 2008. 22 Grewal SPS. Adjunctive use of biodegradable porous collage-glycosaminoglycan implant in phacoemulsification combined with trabeculectomy for surgical management of primary open-angle glaucoma. Presented at: World Ophthalmology Congress 2008. Hong Kong, 28 June–2 July 2008. Affiliations • Joseph R Zelefsky, MD Einhorn Clinical Research Center, New York Eye and Ear Infirmary, 310 East 14th Street, NY 10003, USA; and, New York University Medical Center, New York, NY, USA; and, Manhattan Eye Ear and Throat Hospital, New York, NY, USA • Wei-Cherng Hsu, MD Department of Ophthalmology, Buddhist Tzu Chi General Hospital Taipei Branch, Taipei, Taiwan; and, Department of Ophthalmology, Tzu Chi University, Hualien, Taiwan • Robert Ritch, MD New York Medical College, Valhalla, NY, USA; and, Shelley and Steven Einhorn Distinguished Chair, Einhorn Clinical Research Center, New York Eye and Ear Infirmary, 310 East 14th Street, NY 10003, USA Tel.: +1 212 673 5140 Fax: +1 212 420 8743 [email protected] 617